A major long-term goal of my laboratory is to develop a safe and effective human contraceptive vaccine. To this end, we have taken a two pronged approach: 1) To develop an effective method of reversible contraception, and 2) To assure safety of the vaccine by identifying and resolving potential problems associated with contraceptive vaccination. A chimeric peptide (CP2) that contained a native ZP3 B cell epitope (335-342) and a foreign T cell epitope has proved to be an efficacious vaccine that does not in duce ovarian autoimmune disease in adult animals. CP2 immunization led to 70% reduction in female fertility that was reversible, and their ovaries were free of pathology. However, we have now encountered a new problem associated with the CP2 vaccine. Although the ovaries of adult mice immunized with CP2 were free of pathology, the ovaries of their progeny developed AOD, and in some cases there was loss of oocytes. It is unclear is why progenic AOD [autoimmune ovary disease] should occur only in B6AF 1 neonates but not the neonate of five other inbred strains and one outbred strain. Nor do we understand why progenic AOD should occur only in mice with Ab to one ZP3 B cell epitope [ZP3 (335-342)] but not with Ab to anotherZP3 B epitope [ZP3 (l7I-l80)]. These findings have prompted the hypothesis that progenic AOD represents a unique occurrence confined to a unique mouse strain in response to a unique ZP3 B cell epitope. In the proposed research, we will determine the generalizability of progenic AOD, understand the mechanism of neonatal ovarian injury, elucidate the basis for its unique occurrence, and define its long-term effect. At the same time, our goal is to identify new oocyte antigen (Ag) and examine their potential as candidate Ag in a new, safe and effective ZP contraceptive vaccine. In Aim 1, we will determine the natural history and generalizability of progenic AOD, the fertility of postpubertal mice with a antecedent progenic AOD, the variations in the murine neonatal response to CP2 antibody, and the occurrence of progenic AOD in the primate. Aim 2 will identify new ZP B cell epitopes that confer contraception without progenic AOD. In Aim 3, we will further investigate the mechanism of progenic AOD, and identify the mechanism responsible for the unique occurrence of progenic AOD. Specifically, we will determine the immunogenetic regulation of the immune response to CP2, and the influence of the B cell epitope specificity of the ZP Ab on the induction of progenic AOD.